The Cross-bridge Cycle

Much of our understanding of the mechanism of muscle contraction has come from excellent biochemical studies performed from the 1950s to the mid-1970s (Webb and Trentham, 83). It was during this period that methods for isolating specific muscle proteins were developed as well as the methods for measuring their physicochemical and biochemical properties.

In its simplest form, biochemical experiments on muscle contractile proteins have shown that, during the cross-bridge cycle, actin (A) combines with myosin (M) and ATP to produce force, adenosine diphosphate (ADP) and inorganic phosphate, Pi This can be represented as a chemical reaction in the form

A + M + ATP -> A + M + ADP + Pi + Force (Equation 1)

However, we also know that upon the death of a muscle, a rigor state is entered whereby actin and myosin interact to form a very stiff connection. This can be represented as

A + M -> A.M "rigor" complex (Equation 2)

If actin and myosin can interact by themselves, where does ATP come into the picture during contraction? Experiments have demonstrated that the myosin molecule can hydrolyze ATP into ADP and Pi. In other words,

M + ATP -> M + ADP + Pi (Equation 3)

Scientists now agree that ATP serves at least two functions in skeletal muscle systems: First, ATP disconnects actin from myosin, and second, ATP is hydrolyzed by the myosin molecule to produce the energy required for muscle contraction. This description of the different biochemical steps involved in muscle contraction is referred to as the Lymn-Taylor actomyosin ATPase hydrolysis mechanism. (Webb and Trentham, 83)

The relationship between the Lymn-Taylor kinetic scheme and the mechanical cross-bridge cycle is not fully known. However, Lymn and Taylor proposed that their biochemical data could be incorporated into a four-step cross-bridge cycle that could be envisioned thus:

Cross-bridge Cycle — Download the PostScript
  1. The actin-myosin bridge very rapidly dissociates due to ATP binding to myosin.
  2. The free myosin bridge moves into position to attach to actin, during which ATP is hydrolyzed. (Eq. 3)
  3. The free myosin bridge along with its hydrolysis products rebinds to the actin filament. (Eq. 2)
  4. The cross-bridge generates force, and actin displaces the reaction products (ADP and Pi) from the myosin cross-bridge. This is the rate-limiting step of contraction. The actin-myosin cross-bridge is now ready for the ATP binding of step 1.

It might be appreciated that confirmation of this mechanism would be very difficult indeed! This is currently an active area of muscle biophysical research (Webb and Trentham, 83). One might imagine the difficulty in confirming these elementary mechanical and biophysical reactions. However, a recent advance in biochemistry has allowed direct testing and manipulation of this scheme. The advance involves the development of "caged" compounds--compounds which are inactive in their caged form and become active when the cage is instantaneously removed by a pulse of high-energy laser light (McCray et al., 80). Using caged ATP, single muscle fibers have been subjected to experiments such as those described above and found to behave much as predicted based on the biochemical data (Goldman, 87).

X-ray diffraction was used to determine the crystalline structure of the myosin S1 region (Rayment et al., 1993). Based on the crystallographic structure, S-1 was shown to be a ?back door? enzyme (one in which the substrate [in this case, ATP] and catalyst [in this case, actin] bind on opposite sites of the molecule) and these observations provided a basis on which to propose a molecular mechanism by which ATP binding leads to actin dissociation and force generation. This represents a modification to the scheme presented above and is summarized as follows:

  • In the initial configuration, when myosin and actin are tightly bound, the long cleft connecting the ATP to actin binding site is “closed.” This “rigor” conformation is mutually exclusive with the presence of hydrolyzed ATP on the myosin molecule.
  • ATP binding to myosin changes the shape of the S-1 which is thought to be an “opening” of the cleft. Cleft opening disrupts the interaction between actin and myosin and thus, myosin “lets go” of the actin filament.
  • Hydrolysis of ATP into an intermediate state described as ADP-Pi is accompanied by a conformational change that represents the “cocking” of the cross-bridge while chemical energy from ATP is transferred to the myosin molecule. The molecular details of the cocking are not known.
  • Actin then rebinds to myosin, causing release of the terminal phosphate group of ATP which is believed to allow the myosin molecule to reverse the conformational change while bound to actin, thus providing the power stroke of muscle contraction.

This scheme represents the best synthesis of the available experimental data with the newly obtained structural data. It should be emphasized that a great deal of interpretation and literature synthesis is required to propose this dynamic scheme since only ?snapshots? of the myosin-actin-nucleotide structure are available. Current experiments are being performed with ?artificial? ATP molecules that ?freeze? in a particular configuration (e.g., just after hydrolysis but before inorganic phosphate release) to provide other ?snapshots? of the process.

More details, including some nice animations, can be found on Michael A. Ferenczi's page at the Imperial College in South Kensington.

Another nice animation of the crossbridge cycle can be found at the San Diego State University College of Sciences Human Physiology page.

References

  • Goldman, YE. Kinetics of the actomyosin ATPase in muscle fibers. Ann. Rev. of Physiol. 1987;49:637-654.
  • McCray, JA, Herbette, L, Kihara, T, Trentham, DR. A new approach to time-resolved studies of atp-requiring biological systems: laser flash photolysis of caged ATP. Proc. Natl. Acad. Sci. 1980;77:7237-7241.
  • Webb, MR, and Trentham, DR. Chemical mechanism of myosin-catalyzed ATP hydrolysis. In: Peachy, L.D., Adrian, R.H., and Geiger, S.R., ed. Handbook of Physiology. Bethesda, MD: American Physiological Society.1983;237-255.


Last Updated: Friday, 13-Jan-2006 15:56:13 PST
For questions or comments regarding this site, please e-mail the webmaster.
Copyright © 2000, University of California Regents. All rights reserved.